Addition of calcitonin gene-related peptide (CGRP) to rat glomerular mesangial cells in culture resulted in an increase in cyclic adenosine monophosphate (cAMP) accumulation in a concentration-dependent fashion with an EC50 of approximately 3 nM. Inclusion of CGRP8-37, a CGRP1 selective antagonist shifted CGRP concentration-response curve to the right, suggesting the presence of CGRP1 subtype receptors in these cells. Pretreatment of these cells with CGRP followed by washing and rechallenge with CGRP or isoproterenol or forskolin resulted in selective attenuation of CGRP-mediated cAMP accumulation by 55-60% without affecting isoproterenol or forskolin-mediated accumulation, suggesting that CGRP pretreatment of mesangial cells induced homologous desensitization. CGRP-mediated desensitization of cAMP accumulation was found to be both concentration- and time-dependent. Desensitization did not affect the EC50 of CGRP for stimulation of cAMP accumulation, but resulted in a 55-60% reduction in maximal response. CGRP-mediated desensitization was fast, with half-maximal desensitization occurring as early as 5 min after pretreatment with CGRP. In addition, CGRP-mediated desensitization was blocked by the CGRP receptor antagonist, CGRP8-37, when included in the pretreatment protocol. These data suggest that rat mesangial cells display CGRP1 subtype receptors and that prolonged pretreatment of these cells with CGRP resulted in homologous desensitization.